Epigenetics Research Laboratory, Institute of Nano Science and Technology, Knowledge City, Sector 81, Mohali, Punjab 140306, India.
Epigenetics Research Laboratory, Institute of Nano Science and Technology, Knowledge City, Sector 81, Mohali, Punjab 140306, India.
Carbohydr Polym. 2024 Dec 15;346:122575. doi: 10.1016/j.carbpol.2024.122575. Epub 2024 Aug 3.
Many neurodegenerative and psychiatric malignancies like Parkinson' disease (PD) originate from an imbalance of 17β-Estradiol (E2) in the human brain. However, the peripheral side effects of the usage of E2 for PD therapy and less understanding of the molecular mechanism hinder establishing its neurotherapeutic potential. In the present work, systemic side effects were overcome by targeted delivery using Dopamine receptor D3 (DRD3) conjugated E2-loaded chitosan nanoparticles (Ab-ECSnps) that showed a promising delivery to the brain. E2 is a specific calpain inhibitor that fosters neurodegeneration by disrupting mitochondrial function, while B-cell-specific Moloney murine leukemia virus integration region 1 (BMI1), an epigenetic regulator, is crucial in preserving mitochondrial homeostasis. We showed the administration of Ab-ECSnps inhibits calpain's translocation into mitochondria while promoting the translocation of BMI1 to mitochondria, thereby conferring neurotherapeutic benefits by enhancing cell viability, increasing mitochondrial DNA copy number, and preserving mitochondrial membrane potential. Further, we showed a novel molecular mechanism of BMI1 regulation by calpain that might contribute to maintaining mitochondrial homeostasis for attenuating PD. Concomitantly, Ab-ECSnps showed neurotherapeutic potential in the in vivo PD model. We showed for the first time that our brain-specific targeted delivery might regulate calpain-mediated BMI1 expression, thereby preserving mitochondrial homeostasis to alleviate PD.
许多神经退行性和精神疾病，如帕金森病（PD），起源于人类大脑中 17β-雌二醇（E2）的失衡。然而，E2 用于 PD 治疗的外周副作用以及对分子机制的理解不足，阻碍了其神经治疗潜力的建立。在本工作中，通过使用多巴胺受体 D3（DRD3）缀合的载有 E2 的壳聚糖纳米颗粒（Ab-ECSnps）进行靶向递送，克服了全身副作用，该纳米颗粒显示出有希望递送到大脑。E2 是一种特定的钙蛋白酶抑制剂，通过破坏线粒体功能促进神经退行性变，而 B 细胞特异性莫洛尼鼠白血病病毒整合区 1（BMI1）是维持线粒体动态平衡的关键表观遗传调节剂。我们表明，Ab-ECSnps 的给药抑制钙蛋白酶向线粒体的易位，同时促进 BMI1 向线粒体的易位，从而通过增强细胞活力、增加线粒体 DNA 拷贝数和维持线粒体膜电位来提供神经治疗益处。此外，我们展示了钙蛋白酶调节 BMI1 的新分子机制，这可能有助于维持线粒体动态平衡以减轻 PD。同时，Ab-ECSnps 在体内 PD 模型中显示出神经治疗潜力。我们首次表明，我们的大脑特异性靶向递送可能调节钙蛋白酶介导的 BMI1 表达，从而维持线粒体动态平衡以减轻 PD。
